In recent years, due to the increasing competition in modern society, the increased life stress, more and more serious environment pollution and so on, the morbidity and mortality of malignant tumor are higher than ever before, which makes tumor the second leading cause of death. Therefore, it is of high significance to develop drugs for the treatment of tumor.
Andrographolide (AD), a kind of diterpene lactone compounds extracted from Andrographis paniculata (Burm. f.) Nees which has long been widely used as a folk remedy to alleviate inflammatory disorders in Asia exhibits multiple pharmacological activities. It can be used for the treatment of various ailments, including fever, inflammation, bacterial dysentery, viral infection, tumor, etc. As for the anti-tumor effect, present studies are mainly focused on improving the cytotoxic activity by structural modification or clarifying the mechanism of apoptosis induced by AD. Dr. Reddy's Laboratories LTD has applied for a patent entitled “Preparation and antitumor activity of andrographolide derivs” (WO 2001057026; CN 1416428) to protect the applications of some andrographoide derivatives to the treatment of cancer, infections of HSV or HIV, or psoriasis. The First Affiliated Hospital of Peking University has disclosed the inhibitory effect of diterpene lactone compounds from Andrographis paniculata on angiogenesis in the patent (CN 1511522). A patent applied by Henan University, “A drug combination containing isoandrographolide and its medical uses” (CN 1785177), relates to a drug combination which takes isoandrographolide as the active component containing the pharmaceutically acceptable carrier and its use in the preparation of anti-inflammatory or anti-tumor drugs. A patent applied by Guang Han, “A drug combination containing 3, 14, 19-triacetyl-andrographolide and its medical uses” (CN 101129354), relates to a drug combination which takes 3, 14, 19-triacetyl-andrographolide as the active component containing pharmaceutically acceptable carrier and its use in the preparation of anti-inflammation, immunosuppression and anti-tumor drugs. Hutchison MediPharma Limited has applied for a patent, entitled “the medicinal use of andrographolide, its derivatives and analogs” (CN 1666985), which involves the use of this kind of compounds or their prodrugs in the preparation of TNF-α and/or IL-1β inhibitor.
Indian scientists Nanduri and others synthesized nearly 100 kinds of derivatives by modifying andrographolide at the hydroxyls of C-3, C-14, C-19, and confirmed that these compounds had obvious inhibitory effects on the proliferation of a variety of human cancer cells in vitro, such as MCF-7 breast cancer, SW-620 and HT-29 colon cancer, H522 lung cancer, UACC62 and M14 melanoma, SKOV-3, OVCAR and PA1 ovarian cancer, DU145 and PC-3 prostate cancer, and A498 and ACHN renal cell carcinoma. Showed by the research of Srinivas, et al., the exocyclic Δ8(17) double bond of andrographolide may not play any important role and can be replaced with an epoxy moiety, and then the cytotoxicity significantly improved when further convert these derivatives to esters. Xinyang Wang, et al., synthesized 21 new isoandrographolide dioxalyl esters or dioxalyl amides, and found that 3,19-di{(n-butylamine) carbonyl carboxyl}-O-isoandrographolide was to possess similar antitumor activity and better chemical stability to andrographolide through assay the cytotoxicity by MTT method. Hao Xu, et al., synthesized N-acetyl-12-aminomethyl-14-deoxy andrographolide derivatives (4a-4j) and then appraised the anti-tumor activity of them, and confirmed that all of the ten compounds showed cytotoxicity against BGC823 and SGC-7901 human gastric adenocarcinoma cells and SMMC7721 human hepatoma cells in different levels. The inhibitory effect of compound 4c on SMMC7721 hepatocellular carcinoma is stronger than that of andrographolide, which is similar to that of cisplatin.
However, the structure modifications above were mainly performed at the hydroxyls of C-3, C-14, C-19, and the double bond of Δ8,Δ12, etc. It is of great significance for the application of these compounds and for the protection of our independent intellectual property rights to study the antitumor effect of the C15-substituted analogues of andrographolide.